In 1995, the availability of potent antiretroviral therapy changed the management of HIV infection forever. At that time, "drug cocktails" of medications became the standard of care, with the ultimate goal being long-term viral suppression. The subsequent years brought the realization, however, that long-term antiretroviral therapy also had its limitations, such as the development of drug resistance and toxicity. Nevertheless, simultaneously, major advances were being made in the understanding of HIV immunology.

For example, studies demonstrated that during the first months of infection, the body ordinarily mounts an immune (defensive) response to the virus. This response results in variable levels of viral control. Yet, notably, in rare cases, without therapy, the immune system is able to suppress the viral load to very low levels for prolonged periods of time. These fortunate, albeit rare, individuals have been referred to as long-term nonprogressors. On the other hand, when the virus is suppressed by antiretroviral therapy, the body's natural immunity is not stimulated by the presence of virus in the blood, and thus, the immunity declines.

This important immunologic data provided a scientific rationale for considering interruption of antiretroviral therapy. The idea of interrupting treatment is to allow the viral load to increase and thereby, stimulate the body's immune response to the virus. In other words, the virus already in the body stimulates the body's immune response in a reaction referred to as "autoimmunization." (You see, "auto" means self.) With a regular immunization, in contrast, the virus, previously rendered harmless, is injected into the body to generate the immune response. Accordingly, the goal of this strategy of autoimmunization is to allow the immune system itself to control viral replication (reproduction) after therapy was interrupted.

Investigators have also proposed other goals for the interruption of treatment. For example, the suggestion has been made that patients who have developed resistance to their antiretroviral therapy may be able to stop the therapy to allow the resistant virus to "go away." Then, a new drug regimen can be started with enhanced viral suppression. Finally, others have proposed serial interruptions of therapy to minimize the amount of time people are actually taking their medications. The hope here is that the diminished time on the drugs will result in less toxicity for the patient.

So, the goals of interrupting therapy in these different situations differ. Yet, despite these important differences, each of these strategies has been described in a similar way, as "strategic, structured, or scheduled" treatment interruptions, often abbreviated as STI. The problem is that this one term, STI, has been used loosely to describe various situations. As a result, this use of the term STI has led to considerable confusion among patients and their doctors.

Consequently, it is vital that people understand certain key aspects of each of these different strategies. For instance, for each situation, people need to know the circumstances under which STI is being explored, the data supporting the use of STI, and the potential risks of STI. Below, I have outlined the situations in which interruption of treatment, or STI, is currently being considered.

1. Patients treated during the primary HIV infection, and who have undetectable viral loads.

This situation is unique to the relatively rare individuals that are diagnosed with HIV, and treated during the first weeks or months of the primary (initial) infection. The time of treatment does not refer to the time from when the HIV was first diagnosed by an antibody test. Rather, it refers to the time from when the transmission (spread and acquisition) of HIV actually occurred. In this situation, early treatment that results in undetectable viral loads is believed to preserve the natural immune response to HIV. Also, allowing the viral load to rebound (bounce back) after stopping treatment, should stimulate the immune system to control the HIV. What's more, subsequent interruption(s) of treatment, should ultimately allow the discontinuation of therapy.

In fact, there is limited, yet intriguing, data in this setting suggesting that a subset of patients may actually control the viral load after one or more interruptions of treatment. While still considered experimental, this early treatment of primary HIV with STI is a promising area of ongoing research. Those individuals who are treated or diagnosed during the primary HIV infection should seek out research settings where they can participate in innovative studies related to this stage of the disease.

2. Patients treated at a time after primary HIV infection, and who have undetectable viral loads.

Rationale # 1: To stop therapy in patients that started treatment when the numbers of CD4 cells were high and viral loads were low. The numbers of CD4 cells reflect the status of the body's immune system. Thus, the higher the number of CD4 cells, the stronger is the immune system, and the lower the number, the weaker (more suppressed) is the immune system. I discussed this issue in some detail in my March Doctors Column.

Briefly, new guidelines have supported the possibility of delaying the start of therapy until CD4 cells are less than 350, or if higher, when the viral load is greater than 30-65,000 copies/ml. Remember that these are only guidelines, and should not replace the judgment of individual patients and their physicians. Nevertheless, this new approach has led many people to reconsider the need to stay on therapy.

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At the current time, however, limited data are available to provide guidance to patients and doctors in this situation. Most experts would agree that if the person is doing well on therapy with good tolerance of the drug and adherence to the regimen, it is probably best to continue treatment until more information becomes available. On the other hand, if tolerance is poor, or there are concerns regarding adherence, serious consideration should be given to a change in therapy, including the possibility of discontinuing treatment with close follow-up.

Rationale # 2: To boost immune responses to HIV in order to enhance viral control when off antiretroviral therapy. In this situation, several studies have shown that immune responses can actually be enhanced when therapy is stopped and viral rebound occurs. Evidence showing that this enhanced immune response is associated with improved virologic control, however, is not very encouraging. Accordingly, most researchers agree that this approach remains experimental. As a matter of fact, generally little optimism exists that it will result in clinically relevant benefits for patients. In addition, the paramount concern remains that stopping and then re-starting therapy can result in the development of drug resistance.

Rationale # 3: The goal is not to discontinue (stop) treatment, but cycle (interrupt and restart) it so that the actual time on therapy can be decreased. This concept currently is being explored in small studies where treatment is started and stopped at weekly or monthly intervals. The amount of experience with this approach, however, is extremely limited. While there are always concerns regarding the development of resistant virus when therapy is discontinued, it is particularly worrisome in this setting. Most experts, therefore, would agree that this is not a strategy to consider in clinical practice until more research is completed.

3. Chronic infection with multi-drug resistant virus and poor viral control.

Stopping therapy in this setting has been shown often, although not always, to result in a drug susceptible virus becoming the predominant strain in blood. In all likelihood, the resistant virus persists, but only as a minor population that may not be measurable with the assays available to test for resistant virus. Whether this switch in the predominant virus will allow for enhanced viral control upon reinitiating therapy is being studied. At this time, the amount of experience demonstrating benefit from this approach is too small to draw any conclusions.

In the two settings described above, interruption of therapy is done at a time of full viral suppression, and the potential for developing drug resistance, therefore, is very real. By contrast, in this situation, where the patients already have multi-drug resistant virus, they are not likely to develop increased drug resistance. However, since these patients often have more advanced HIV disease, with lower CD4 cell counts, they may experience precipitous declines in CD4 cells during the interruption of treatment. The resulting weakening of the immune system may place them at increased risk for developing opportunistic infections or other complications of AIDS. Thus, if therapy is discontinued in this setting, the immune status should be monitored closely, and patients should receive appropriate prophylaxis (preventative medications) for infections.

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In conclusion, STIs have become a fascinating new strategy to deal with several aspects of HIV disease. Many studies are now underway to address the role of STIs in various clinical situations. As a clinician my objective is to make sure that patients are fully informed of the status of this research and the potential risks and benefits of such interventions. It remains important that people distinguish between therapeutic strategies under investigation and those that have been proven to be safe and effective. For now, STI clearly falls in the former category.

Medical Author: Eric S. Daar, M.D.

Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.